The proposed project will continue our study of those biochemical changes that are early, critical events in the onset of virus-induced leukemia by employing AKR mice that carry an oncornavirus. A second model for leukemogenesis that will be employed is a chemically induced lymphoma produced by a single injection of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide. Particular emphasis will be placed on those changes that occur in the preleukemic state and that eventually allow the establishment of the leukemic clone. Initial results from this laboratory have indicated many enzymatic differences between normal thymus cells and cells of the lymphoma. On the other hand, the only detectable change in the preleukemic state, with no overt signs of leukemia, was an elevation of adenylate cyclase and cyclic AMP. The proposal will test our hypothesis that the expansion of the leukemic clone in the thymus requires the turning off of the normal immune response and of the proliferation of normal lymphocytes by producing elevated levels of cyclic AMP in these cells. The clone itself is protected by a high activity of cyclic AMP phosphodiesterase and is thus capable of overgrowing the normal cells. Experiments to test this hypothesis will examine biochemical parameters in short term culture of thymus cells as well as measurements of enzymatic activities in cell extracts. Measurements of cyclic GMP, guanylate cyclase, and cyclic GMP phosphodiesterase will also be performed with cells from normal, preleukemic, and leukemic mice. The study will hopefully provide a focal point for interfering with the chain of metabolic events that results in the virus-induced malignant evolution of lymphoid cells.